Sodium hydride (NaH) is widely used as a Brønsted base in chemical synthesis and reacts with various Brønsted acids, whereas it rarely behaves as a reducing reagent through delivery of the hydride to polar π electrophiles. This study presents a series of reduction reactions of nitriles, amides, and imines as enabled by NaH in the presence of LiI or NaI. This remarkably simple protocol endows NaH with unprecedented and unique hydride‐donor chemical reactivity.

Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre-Pparb/d−/−) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d−/− mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis.

Sodium hydride (NaH) has been commonly used as a Brønsted base in chemical syntheses, while it has rarely been employed to add hydride (H(-) ) to unsaturated electrophiles. We previously developed a procedure to activate NaH through the addition of a soluble iodide source and found that the new NaH-NaI composite can effect even stereoselective nucleophilic hydride reductions of nitriles, imines, and carbonyl compounds. In this work, we report that mixing NaH with NaI or LiI in tetrahydrofuran (THF) as a solvent provides a new inorganic composite, which consists of NaI interspersed with activated NaH, as revealed by powder X-ray diffraction, and both solid-state NMR and X-ray photoelectron spectroscopies. DFT calculations imply that this remarkably simple inorganic composite, which is comprised of NaH and NaI, gains nucleophilic hydridic character similar to covalent hydrides, resulting in unprecedented and unique hydride donor chemical reactivity.

Sodium hydride (NaH) is widely used as aBrønsted base in chemical synthesis and reacts with various Brønsted acids,whereas it rarely behaves as areducing reagent through delivery of the hydride to polar p electrophiles.T his study presents aseries of reduction reactions of nitriles,amides,and imines as enabled by NaH in the presence of LiI or NaI. This remarkably simple protocol endows NaH with unprecedented and unique hydride-donor chemical reactivity.Hydridereductionofpolarp electrophiles,such as carbonyl compounds,c arbonitriles,a nd imines,i so ne of the most fundamental and important molecular transformations in chemical synthesis.[1] In this context, av ariety of covalent hydrides,s uch as borane,a lane,m etal borohydrides,m etal aluminum hydrides,and silanes,have often been employed as the reagents of choice for stereo-, regio-, and chemoselective hydride-transfer processes.Bycontrast, alkali-metal hydrides have rarely been employed as hydride sources;i nstead, they are used almost exclusively as strong Brønsted bases for deprotonation reactions in chemical synthesis. [2,3] Herein, we report that NaH can act as ahydride donor in reactions with nitriles,a mides,a nd imines when it has been subjected to simple solvothermal treatment with LiI or NaI in THF.O f particular interest is the outcome of hydride reduction reactions of nitriles and amides,w hich deliver the corresponding alkanes (through decyanation) and aldehydes, respectively.During the course of our experiments on the a-methylation of diphenylacetonitrile (1)t op repare tertiary carbonitrile 2a,weinvestigated its reaction with NaH (3 equiv) and MeI (1.2 equiv) in THF (85 8 8Ci nas ealed tube;S cheme 1). Although the desired tertiary nitrile 2a was isolated in 74 % yield, we were surprised to observe the formation of 1,1-diphenylethane (3a)i n2 5% yield as aside product. Assuming that 3a was formed by the decyanation of nitrile 2a,w e expected that this decyanation reaction could be generalized to am ore versatile synthetic strategy

[n]Cyclo-para-phenylene congeners of n = 12, 16, 20 with n/2 nitrogen atoms were synthesized via Pt-mediated one-pot macrocyclization reactions. The reaction allowed diversification of participating arylene numbers to afford a series of nanohoop molecules. Spectroscopic analyses in solution showed arylene rotations, and crystallographic analyses in crystals revealed an interesting packing motif. The nanohoop molecules were interwoven by the alkyl substituents in a thread-in-bead manner to form nanoporous packing structures in the crystal.is an interesting class of compounds.1 The [n]CPP macrocycles with para-linked phenylene units result in a unique hoop-shaped molecular structure possessing aromatic panels stood in parallel with the cylindrical axis of the molecule in the crystalline solid state. 13 Because of increasing interest in the structures of [n]CPP, a wide range of structural variations has quickly been accumulated within the past few years.4 Driven by our own curiosity, 3,5 we started utilizing large polycyclic aromatic hydrocarbons to design and synthesize belt-persistent macrocycles 5 and demonstrated that the tubular structures provided unique nanosized spaces to accommodate various guests. 6 In this Letter, we report π-extended, nitrogen-embedded [n]CPP congeners. The synthesis relied on the unexpected, favorable effects of an azaaromatic panel on Pt-mediated macrocyclization reactions.1c,5a We found that macrocyclization was effective in the presence of multiple (n/2) coordinating nitrogen atoms, and the number of participating units was randomized. 7,8 The nitrogen atoms also served as a probe for the dynamic behaviors to reveal rapid rotations of the arylene panels. Crystallographic analysis of one of the nitrogen-embedded congeners revealed that we may design porous organic crystals by utilizing the large hoop-shaped structure in combination with interwoven packing structures.The Pt-mediated macrocyclization reaction of arylene panels comprising one pyrenylene 2k,9 and two phenylene units was first examined for π-extension but failed to afford the desired macrocycles. 5 We synthesized a basic pyrenylene unit 2 with two borylated phenylene groups from brominated precursor 1 and subjected it to a macrocyclization reaction with [PtCl 2 (cod)] (Scheme 1a). Unexpectedly, we could not detect any macrocyclic Pt-complexes by MS analysis of the crude mixture. As an assignable species, we detected only an L-shaped biarylated Pt-complex.As an alternative arylene motif, we next introduced diazapyrenylene by adopting a synthetic strategy developed by one of the authors.10 A concise synthesis route for bromophenylated 1,8-diazapyrene 3 allowed us to introduce two nitrogen atoms and two hexyl substituents in the precursor unit for macrocyclization (Scheme 1b). Thus, after transforming 3 into a borylated synthetic intermediate 4 via Miyaura borylation with 30 mol % of [Pd(dppf)Cl 2 ]¢CH 2 Cl 2 (dppf: 1,1¤-bis(diphenylphosphino)ferrocene), we examined the platinum-mediated macrocyclization. Previous reactio...